Understanding the Multiple Roles of Extracellular Histones in Mediating Endothelial Dysfunction
Authors: Tinghang Yang, Yupei Li, Baihai Su
Journal: Journal of the American Society of Nephrology (2022)

We read with great interest a recent article entitled "Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms" by Arnaud et al.1 The authors demonstrated that extracellular histones correlate with AKI severity and mortality in patients with tumor lysis syndrome and that they mediate tumor lysis syndrome–induced endothelial dysfunction. Although the authors briefly proposed that Toll-like receptor 4 (TLR-4) was involved in modifying adhesion molecule expression and IL-6/IL-8 secretion by endothelial cells (ECs) and inducing renal endothelial microvascular leakage, here we intend to add further discussion to fuel the understanding of the multiple roles of histones in mediating endothelial dysfunction. Extracellular histones are recently identified damage-associated molecule patterns in multiple critical illnesses, such as sepsis, trauma, pancreatitis, and severe coronavirus disease 2019.2 Growing evidence shows that histones exhibit significant cytotoxicity to ECs in a dose- and time-dependent manner, and that they play multiple roles in mediating endothelial dysfunction in intestinal, cerebral, and pulmonary microcirculation.2 First, administration of exogenous histones may cause either endothelial pyroptosis, by inducing oxidative stress and activating the NLRP3 inflammasome, or direct cytotoxicity to ECs, by altering membrane permeability and initiating calcium ion influx. Second, low-dose histones induce autophagy and apoptosis of ECs via mammalian target of rapamycin signaling.2 Third, histones could induce the degradation of endothelial glycocalyx, such as heparan sulfate and syndecan-1 through the heparinase pathway. Fourth, histones remarkably activate ECs to increase tissue factor expression, leading to the activation of the coagulation cascade and complement system in patients who are critically ill.2 More recently, the roles of extracellular histones in mediating the expression and function of intracellular adherens junction proteins, such as VE-cadherin and p120-catenin, have been reported. For instance, Biswas et al.3 found that histones exhibited proapoptotic effects, by eliciting nuclear localization of PKC-δ, and barrier-disruptive effects, by increasing VE-cadherin phosphorylation in ECs. Likewise, Karki et al.4 showed that histone H3 induced a dramatic loss of VE-cadherin in lung endothelium, with increased protein expression of inflammatory adhesion molecules, including intercellular adhesion molecule-1, vascular cell adhesion molecule 1, and E-selectin through the NF-κB pathway, which could be significantly inhibited with a specific TLR-4 inhibitor. According to these published data, we hypothesize that histones may affect the integrity of the endothelial barrier by reducing intercellular junctions and reorganizing the actin cytoskeleton via the histone–TLR-4–VE-cadherin pathway. However, definite molecular mechanisms remain to be explored in the future to provide solid evidence for therapeutic intervention of AKI by targeting extracellular histones. Disclosures All authors have nothing to disclose. Funding This work was financially sponsored by the Sichuan Science and Technology Program, grant 2022YFS0147; and the 1.3.5 Project for Disciplines of Excellence from West China Hospital of Sichuan University, grant ZYJC21010.